A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression | Zendy

Rajat M. Gupta | Zendy; Joseph Hadaya | Zendy; Aditi Trehan | Zendy; Seyedeh M. Zekavat | Zendy; Carolina Roselli | Zendy; Derek Klarin | Zendy; Connor A. Emdin | Zendy; Catharina R.E. Hilvering | Zendy; Valerio Bianchi | Zendy; Christian Mueller | Zendy; Amit V. Khera | Zendy; Russell J.H. Ryan | Zendy; J Engreitz | Zendy; Robbyn Issner | Zendy; Noam Shoresh | Zendy; Charles B. Epstein | Zendy; Wouter de Laat | Zendy; Jonathan D. Brown | Zendy; Renate B. Schnabel | Zendy; B Bernstein | Zendy; Sekar Kathiresan | Zendy

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A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression

Author(s) -

Rajat M. Gupta,

Joseph Hadaya,

Aditi Trehan,

Seyedeh M. Zekavat,

Carolina Roselli,

Derek Klarin,

Connor A. Emdin,

Catharina R.E. Hilvering,

Valerio Bianchi,

Christian Mueller,

Amit V. Khera,

Russell J.H. Ryan,

J Engreitz,

Robbyn Issner,

Noam Shoresh,

Charles B. Epstein,

Wouter de Laat,

Jonathan D. Brown,

Renate B. Schnabel,

B Bernstein,

Sekar Kathiresan

Publication year - 2017

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2017.06.049

Subject(s) - biology , genetics , genome wide association study , epigenomics , epigenetics , enhancer , gene , genetic association , gene expression , single nucleotide polymorphism , dna methylation , genotype

Genome-wide association studies (GWASs) implicate the PHACTR1 locus (6p24) in risk for five vascular diseases, including coronary artery disease, migraine headache, cervical artery dissection, fibromuscular dysplasia, and hypertension. Through genetic fine mapping, we prioritized rs9349379, a common SNP in the third intron of the PHACTR1 gene, as the putative causal variant. Epigenomic data from human tissue revealed an enhancer signature at rs9349379 exclusively in aorta, suggesting a regulatory function for this SNP in the vasculature. CRISPR-edited stem cell-derived endothelial cells demonstrate rs9349379 regulates expression of endothelin 1 (EDN1), a gene located 600 kb upstream of PHACTR1. The known physiologic effects of EDN1 on the vasculature may explain the pattern of risk for the five associated diseases. Overall, these data illustrate the integration of genetic, phenotypic, and epigenetic analysis to identify the biologic mechanism by which a common, non-coding variant can distally regulate a gene and contribute to the pathogenesis of multiple vascular diseases.

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